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In Small Patient Group, Sarepta’s DMD Gene Therapy Gives Some Hope

Sarepta Therapeutics’ experimental gene-therapy treatment for Duchenne muscular dystrophy (DMD) is showing some early signs of promise. Patients who received the therapy are showing increasing signs of a muscle protein that had been missing, the company said.

Data presented at the 23rd International Congress of the World Muscle Society in Mendoza, Argentina by Cambridge, Mass.-based Sarepta, showed “robust expression of transduced micro-dystrophin,” the company announced late Wednesday. Sarepta said mean gene expression for the study, as measured by percentage of micro-dystrophin positive fibers was 81.2 percent and the mean intensity of the fibers was 96 percent compared to normal control. Additionally, the company said post-treatment biopsies showed robust levels of micro-dystrophin as measured by Western blot. The biopsies revealed a mean of 74.3 percent compared to normal utilizing Sarepta’s method, or 95.8 percent compared to normal pursuant to Nationwide Children’s quantification of Sarepta’s method that adjusts for fat and fibrotic tissue.

Sarepta said the fourth patient who underwent the treatment responded in a stellar way. The patient’s micro-dystrophin positive fibers were 96.2 percent and the mean intensity of the fibers was 160 percent compared to normal control.

In addition, Sarepta said patients who received the gene therapy showed mobility improvements in various ambulatory tests, including Time to Rise and 4 Stairs Up. Sarepta said the boys demonstrated significant improvement within the first 90 days of treatment. While Sarepta pointed to the improvements, the company was quick to caution that the results are from an uncontrolled data set and these positive results must be reconfirmed in the larger, controlled registration trial.

In all patients, expression of micro-dystrophin was associated with significant expression and up-regulation of the dystrophin-associated protein complex, an additional indication of functionality of dystrophin, Sarepta said.

“The goal of this study was to validate what we observed in pre-clinical models. We observed efficient transduction of our vector, AAVrh74, to all muscle types; robust expression in skeletal muscles via the MHCK7 promoter; a reduction in creatine kinase levels; and a favorable safety profile,” lead investigator Jerry Mendell said in a statement. “Similar to pre-clinical models, we also observed in this early study that robust expression has the potential to positively impact the natural course of disease progression.”

DMD is associated with specific errors in the gene that codes for dystrophin, a protein that plays a key structural role in muscle fiber function. Progressive muscle weakness in the lower limbs spreads to the arms, neck and other areas. Eventually, increasing difficulty in breathing due to respiratory muscle dysfunction requires ventilation support, and cardiac dysfunction can lead to heart failure. One of the most common fatal genetic disorders, DMD affects approximately one in every 3,500 boys born worldwide. The condition is universally fatal, and death usually occurs before the age of 30.

Sarepta Chief Executive Officer Doug Ingram called the results encouraging. He added that the data seen in Patient 4 strengthened the company’s resolve to “move to a confirming trial and, assuming successful, to bring this therapy to the Duchenne community around the world with a sense of urgency.”

In September the U.S. Food and Drug Administration (FDA) lifted a clinical hold it had placed on Sarepta’s DMD micro-dystrophin gene therapy program. The FDA had placed the hold in July following the discovery of trace amounts of DNA fragment in research-grade third-party supplied plasmid in a manufacturing lot. As BioSpace reported in July, patients had not been treated with the contaminated lot, but patients had been treated with different lots from the same supplier.